1. Field of the Invention
The present invention relates to novel compounds and processes. In particular, the invention relates to novel analogs of the aminocyclitol antibiotic spectinomycin and novel processes and intermediates for synthesizing these novel analogs.
The novel analogs of spectinomycin disclosed herein are useful as antimicrobial agents and the novel intermediates are useful in synthetic processes for making the novel antimicrobial analogs.
Spectinomycin is the compound illustrated, with numbering of carbon positions, in formula XX.
The present invention relates to novel C-3' analogs of
(i) spectinomycin (formula XX),
(ii) C-6' analogs of spectinomycin, including the 5'-desmethyl analog, of spectinomycin illustrated in formula XXI wherein R.sub.3 is: PA1 (iii) analogs of spectinomycin (formula XX) and C-6' analogs thereof (formula XXI) in which the hydrogen atom attached to each of the nitrogen atoms bonded to C-1 and C-3 in the molecules are replaced by a blocking group. PA1 (i) the novel, base-catalyzed synthesis of novel 3'-deoxo-3'-diazo analogs of spectinomycin from known 3'-deoxo-3'-arylsulfonylhydrazone analogs of spectinomycin; PA1 (ii) the novel synthesis of novel 3'-deoxo-3'-(N,N'-dialkyl)-enamino-analogs of spectinomycin from novel 3'-deoxo-3'-diazo analogs thereof and (N,N-dialkyl)methyleneammonium halides in the presence of base in dry acetonitrile or other lower-alkyl-cyanide solvents; PA1 (iii) the novel synthesis of both 3'-(R)-spectinomycin cyanohydrins and 3'-(S)-spectinomycin cyanohydrins from the corresponding spectinomycins themselves (with keto-oxygen at C-3') and a source of cyano groups (e.g., hydrogen cyanide or acetone cyanohydrin) in the presence of base or basic ion exchange resin; and PA1 (iv) the novel synthesis of 3'-(S)-spectinomycin cyanohydrins from the corresponding 3'-(R)-spectinomycin cyanohydrins in the presence of base or basic ion exchange resin. PA1 (a) hydrogen or PA1 (b) a blocking group; PA1 wherein R.sub.3 is PA1 (a) hydrogen PA1 (b) alkyl of 1 to 8 carbon atoms, inclusive, PA1 (c) --R.sub.31 --O--R.sub.32, wherein R.sub.31 is alkylene of 1 to 4 carbon atoms, inclusive, and R.sub.32 is hydrogen or alkyl of 1 to 6 carbon atoms, inclusive, with the proviso that the sum of the number of carbon atoms in R.sub.31 and the number of carbon atoms in R.sub.32 is less than or equal to 7, PA1 (d) --R.sub.31 --NR.sub.33 R.sub.34, wherein R.sub.31 is as defined above, wherein R.sub.33 is hydrogen or alkyl of 1 to 6 carbon atoms, inclusive, and R.sub.34 is hydrogen, alkyl of 1 to 6 carbon atoms, inclusive, or a blocking group, with the proviso that if R.sub.34 is not a blocking group, the sum of the number of carbon atoms in R.sub.31 and the number of carbon atoms in whichever of R.sub.33 or R.sub.34 has the larger number of carbon atoms is less than or equal to 7, or PA1 (e) alkyl of 1 to 4 carbon atoms, inclusive, substituted with 1, 2, or 3 halogen atoms; PA1 wherein A is PA1 (a) .dbd.N.sub.2, PA1 (b) .alpha.--H:.beta.--H, PA1 (c) .alpha.--H:.beta.--X, wherein X is chlorine or bromine, i.e., the configuration at C-3' is (R), PA1 (d) .alpha.--Cl:.beta.--Cl, PA1 (e) .dbd.CH(NR.sub.5 R.sub.6), with the proviso that PA1 (f) .alpha.--CHO:.beta.--H, i.e., the configuration at C-3' is (R), with the proviso that PA1 (g) methylene (.dbd.CH.sub.2), with the proviso that PA1 (h) .alpha.--CH.sub.2 OH:.beta.--H, i.e., the configuration at C-3' is (R), PA1 (i) .alpha.--H:.beta.--CH.sub.2 NR.sub.5 R.sub.6 or .alpha.--CH.sub.2 NR.sub.5 R.sub.6 :.beta.--H, i.e., the configuration at C-3' is (R) or (S) but not both, PA1 (j) .alpha.--CH.sub.2 OH:.beta.--OH, i.e., the configuration at C-3' is (S), PA1 (k) epoxymethano (--O--CH.sub.2 -- or --CH.sub.2 --O--), with the proviso that PA1 (1) .alpha.--OH:.beta.--CH.sub.2 N.sub.3 or .alpha.--CH.sub.2 N.sub.3 :.beta.--OH, i.e., the configuration at C-3' is (R) or (S), with the proviso that PA1 (m) .alpha.--OH:.beta.--(CH.sub.2).sub.m --CN or .alpha.--(CH.sub.2).sub.m --CN:.beta.--OH, wherein m is 0 or 1, i.e., the configuration at C-3' is (R) or (S), PA1 (n) .alpha.--OH:.beta.--(CH.sub.2).sub.p --NR.sub.41 R.sub.42 or .alpha.--(CH.sub.2).sub.p --NR.sub.41 R.sub.42 :.beta.--OH, wherein p is 1 or 2, and R.sub.41 and R.sub.42, being the same or different, are PA1 (a) alkyl of one to 12 carbon atoms, inclusive, or aryl or aralkyl of 7 to 12 carbon atoms optionally substituted by one or two PA1 (b) --R.sub.43 --R.sub.44 wherein R.sub.43 and R.sub.44 are as defined above, or PA1 (c) pyridyl, piperazyl, pyrollyl or morpholinyl optionally substituted by PA1 reacting in an inert organic solvent a compound of formula III wherein R.sub.4 is an aryl group, with an organic amine base. PA1 wherein R.sub.7 is a blocking group; PA1 wherein R.sub.3 is as defined above; PA1 wherein R.sub.5 and R.sub.6, being the same or different, are alkyl of 1 to 6 carbon atoms, inclusive; and PA1 wherein the configuration at the carbon atom to which --NR.sub.5 R.sub.6 is bonded is, with respect to C-2', E or Z but not both, which comprises: PA1 reacting a compound of formula V, wherein R.sub.7 is as defined above, with a compound of formula VI, wherein X.sub.6 is chlorine or bromine, in the presence of a tertiary amine base in a solvent R.sub.8 CN, wherein R.sub.8 is alkyl of 1 to 3 carbon atoms, inclusive. PA1 (a) combining a compound of formula VIII with a compound which is a source of cyano groups, in an unreactive organic solvent in the presence of base or basic ion exchange resin, and PA1 (b) isomerizing at the C-3' position of the compound of the reaction product of step (a) by allowing the reaction product to remain in the solution for a length of time sufficient to result in the formation of a mixture of the compound of formula VII with its C-3' epimer, characterized by an amount of the compound of formula VII which is greater than the amount of its C-3' epimer. PA1 (a) combining a compound of formula VIII with a compound which is a source of cyano groups, in an unreactive organic solvent in the presence of base or basic ion exchange resin, and PA1 (b) permitting reaction of step (a) to proceed in the solution for a length of time sufficient to result in the formation of compound of formula X, and PA1 (c) terminating the reaction of step (b) prior to the formation of an amount of said C-3' epimer which is larger than the amount of said formula X compound by (i) quenching said reaction by the addition of acid to neutralize said base of said basic ion-exchange resin or (ii) removing said ion-exchange resin if no other base is present. PA1 combining a compound of formula X with a base or a basic ion-exchange resin in an unreactive organic solvent. PA1 (a) reaction with an acid anhydride, PA1 (b) reaction with an acid chloride in the presence of base, or PA1 (c) reaction with an acid and a coupling reagent such as dicyclohexylcarbodiimide or an alkylchloroformate. PA1 S. aureus PA1 S. faecalis PA1 E. coli PA1 K. pneumoniae PA1 Ps. aeruginosa PA1 P. vulgaris PA1 P. mirabilis PA1 S. flexneri PA1 S. marcescens PA1 S. schottmuelleri.
(a) hydrogen PA2 (b) alkyl of 2 to 8 carbon atoms, inclusive, PA2 (c) --R.sub.31 --O--R.sub.32, wherein R.sub.31 is alkylene of 1 to 4 carbon atoms, inclusive, and R.sub.32 is hydrogen or alkyl of 1 to 6 carbon atoms, inclusive, with the proviso that the sum of the number of carbon atoms in R.sub.31 and the number of carbon atoms in R.sub.32 is less than or equal to 7, PA2 (d) --R.sub.31 --NR.sub.33 R.sub.34, wherein R.sub.31 is as defined above, wherein R.sub.33 is hydrogen or alkyl of 1 to 6 carbon atoms, inclusive, and wherein R.sub.34 is hydrogen, alkyl of 1 to 6 carbon atoms, inclusive, or a blocking group with the proviso that when R.sub.34 is not a blocking group, the sum of (a) the number of carbon atoms in R.sub.31 and (b) the number of carbon atoms in whichever of R.sub.33 or R.sub.34 has the larger number of carbon atoms is less than or equal to 7, or PA2 (e) alkyl of 1 to 4 carbon atoms, inclusive, substituted with 1, 2, or 3 halogen atoms, PA2 (i) R.sub.1 is a blocking group and PA2 (ii) R.sub.34 is not hydrogen and, if R.sub.33 is hydrogen, R.sub.34 is a blocking group, and wherein R.sub.5 and R.sub.6, being the same or different, are alkyl of 1 to 6 carbon atoms, inclusive, and wherein the configuration at the vinylogous carbon bonded to C-3' is, with respect to C-2', E or Z, but not both, PA2 (i) R.sub.1 is a blocking group and PA2 (ii) R.sub.34 is not hydrogen and, if R.sub.33 is hydrogen, R.sub.34 is a blocking group, PA2 (i) R.sub.1 is a blocking group and PA2 (ii) R.sub.34 is not hydrogen and, if R.sub.33 is hydrogen, R.sub.34 is a blocking group, PA2 (i) R.sub.1 is a blocking group and PA2 (ii) R.sub.34 is not hydrogen and, if R.sub.33 is hydrogen, R.sub.34 is a blocking group, PA2 (i) R.sub.1 is a blocking group and PA2 (ii) R.sub.34 is not hydrogen and, if R.sub.33 is hydrogen, R.sub.34 is a blocking group, PA2 (i) hydrogen PA2 (ii) alkyl of 1 to 12 carbon atoms, inclusive, PA2 (iii) aryl of 6 to 12 carbon atoms, or PA2 (iv) aralkyl of 7 to 12 carbon atoms, inclusive, optionally substituted by one or two PA2 (v) --R.sub.43 --R.sub.44, wherein --R.sub.43 -- is a single bond or R.sub.43 is alkylene of 1 to 4 carbon atoms, inclusive, and R.sub.44 is cycloalkyl of 3 to 10 carbon atoms, inclusive, or R.sub.41 and R.sub.42 taken together with N form a heterocyclic amine ring with 3 to 10 carbon atoms, inclusive, in the ring, or PA2 (vi) --CO--R.sub.45, wherein R.sub.45 is
Unless otherwise qualified, reference herein to a C-3' analog or C-3' analogs of spectinomycin includes reference to the aforementioned analogs with the nitrogen atoms bonded to C-1 and C-3 blocked and to analogs of formula XXI (including analogs of formula XXI with nitrogen atoms bonded to C-1 and C-3 blocked).
Blocking groups as referred to above are sometimes called "protective groups" in the art and are well known in many fields of organic chemistry, including peptide chemistry, fatty acid chemistry and especially semi-synthetic and synthetic antibiotic chemistry. Two commonly used blocking groups are carbobenzyloxy and t-butoxycarbonyl. Such groups can be removed easily and replaced by hydrogen atoms with suitable treatments, which may vary in detail depending on the particular blocking group and the particular molecule to which it is bonded, with acids or by reduction. A quite comprehensive list of blocking groups which can be attached to spectinomycin analogs is disclosed in U.S. Pat. No. 4,173,647, the selection, preparation, use and hydrolysis of which is incorporated herein by reference. Regarding the chemistry of adding and removing such blocking groups, see, e.g., Biossonnas, Adv. Org. Chem. 3, 159 (1963) and Windholz, et al., Tetrahedron Lett., 8, 2555 (1967).
Spectinomycin itself is a known natural product. Bergy, et al., U.S. Pat. No. 3,234,092. Numerous spectinomycin analogs in which the nitrogen atom bonded to C-1 and C-3 are blocked are also known. Maier, et al., U.S. Pat. No. 4,173,647; Federal Republic of Germany Offenlegungschriften Nos. 2,756,912 (Derwent Farmdoc Accession No. 50959B) and 2,756,913 (Derwent Farmdoc Accession No. 50960B).
Numerous C-6' analogs, including the 5'-desmethyl, of spectinomycin as well as such analogs with nitrogen atoms bonded to C-1 and C-3 blocked, are known. U.S. patent application Ser. No. 150,530, filed May 16, 1980 now U.S. Pat. No. 4,351,771.
The present invention also concerns novel synthetic processes. In particular, it concerns:
With respect to novel process (iii), either epimer can be synthesized in excess of the other, depending on reaction conditions (especially reaction time, the base or basic ion-exchange resin used, and the concentration or amount thereof in the reaction mixture) as described in greater detail below. Base catalyzes both hydrocyanation and isomerization at C-3' in novel process (iii).
All of the analogs of the present invention which contain one or more blocking groups, and all of the analogs which contain a diazo group at C-3' are useful intermediates in processes for making C-3' analogs of spectinomycin which are useful as antimicrobial agents.
The present invention also includes the pharmacologically acceptable acid addition salts of the novel antimicrobial C-3' analogs of spectinomycin disclosed herein.
Similar to the known antimicrobial spectinomycin and C-6' spectinomycin-analog precursors, the novel C-3' spectinomycin analogs of the present invention, useful as antimicrobial agents, are either microbistatic or microbicidal. The novel antimicrobial C-3' spectinomycin analogs within the scope of the present invention are useful for inhibiting the growth of, or eliminating, microorganisms in various environments wherein the presence or unchecked growth of the microorganism is undesirable or harmful. Each of the antimicrobial C-3' spectinomycin analogs of the present invention is microbistatic or microbicidal against at least one microorganism in at least one environment in which the presence of the microorganism is undesirable or harmful. Microorganisms against which at least one of the antimicrobial C-3' spectinomycin analogs of the present invention are active include E. coli, K. pneumoniae, S. marcescens, S. typhi, S. faecalis, P. vulgaris, P. mirabilis, Ps. aeruginosa, as well as others, including both gram-negative and gram-positive bacteria. Some of the novel, antimicrobial C-3' spectinomycin analogs of the present invention are also useful for treating or preventing microbial infections in mammals, including humans.
Other than well known deprotection reactions required to replace blocking groups with hydrogen atoms on blocked nitrogen atoms, the chemical transformations disclosed in the present specification occur at C-3'. None of the chemical transformations disclosed in the present specification alter the configuration at any chiral center, other than C-3', from the configuration exhibited by spectinomycin, its actinamine-ring-nitrogen-blocked analogs, or any of the C-6' analogs of spectinomycin (including actinamine-ring-nitrogen-blocked) of concern in the present specification as starting materials in the synthesis of the novel C-3' analogs. Consequently, in many of the structural formulas used in the present specification, only the region of the structure near the C-3' position will be depicted. In such formulas, the portion of the structure not shown, including configurations at chiral centers not shown, is as in spectinomycin (formula XX) or the relevant C-6' analog thereof. The configuration about any chiral center that may be present in a blocking group or a substituent at C-6' is not changed by any of the chemical transformations disclosed in the present specification.
Configurations at C-3' of the novel compounds disclosed herein are specified as either "R" or "S" in accordance with sequence rules well known to the art. Configurations about olefinic double bonds are specified using "E" to designate the trans-configuration and "Z" to designate the cis-configuration utilizing similarly art-recognized procedures for identifying geometric isomers.
2. Prior Art
Several C-3' analogs of spectinomycin, with and without blocking groups on the actinamine-ring nitrogens (i.e., the nitrogens bonded to C-1 and C-3) are known. In aqueous solution, spectinomycin exists as the C-3' ketone hydrate (formula XXII). Wiley, et al., J. Am. Chem. Soc. 85, 2652 (1963).
Wiley, et al., J. Am. Chem. Soc. 85, 2652 (1963) also report the preparation of both C-3' epimers of 3'-dihydro-spectinomycin (formula XXIII).
Knight and Hoeksema, J. Antibiotics 28, 136 (1975), disclose the N,N'-di(carbobenzyloxy) derivative of spectinomycin itself and both epimers of the 3'-dihydro analog. (The nitrogen atoms bonded to C-1 and C-3 are designated herein as N and N', respectively.)
Maier, et al., U.S. Pat. No. 4,173,647, disclose both epimers of 3'-deoxo-3'-amino-3'-dihydrospectinomycin (formula XXIV) and a large number of actinamine-ring-nitrogen-blocked analogs of both including specifically the N,N'-di(carbobenzyloxy), N,N'-di(p-methoxybenzyloxycarbonyl), N,N'-di[(2,2,2-trichloroethoxy)carbonyl], and N,N'-di(isobornyloxycarbonyl) analogs. The Maier, et al. U.S. patent also discloses a large number of actinamine-ring-nitrogen-blocked analogs of spectinomycin itself, including specifically the same five named above for the 3'-deoxo-3'-amino-3'-dihydro-epimers. The Maier, et al. U.S. patent also discloses numerous oximes and hydrazones of spectinomycin and numerous actinamine-ring-nitrogen-blocked analogs of spectinomycin. The patent discloses specifically spectinomycin benzyloxime and the N,N'-di(carbobenzyloxy) analog thereof, the N,N'-di(carbobenzyloxy) analog of spectinomycin methyloxime, spectinomycin benzylhydrazone and spectinomycin acethydrazone.
Numerous oximes and hydrazones of spectinomycin, and actinamine-ring-nitrogen-blocked analogs thereof, are also disclosed in Federal Republic of Germany Offenlegungschrift No. 2,756,912, published July 5, 1979 and abstracted at Derwent Farmdoc Accession No. 50959B. Methylsulfonylhydrazone and (p-toly)sulfonylhydrazone (i.e., tosylhydrazone) of spectinomycin and many of its N,N'-diblocked analogs are described in German Offenlegungschrift No. 2,756,912.
Formula XXV shows the C-3'-region of spectinomycin hydrazone, a compound generically disclosed in U.S. Pat. No. 4,173,647. Formula XXVI shows the C-3' region of spectinomycin tosylhydrazone.
Maier, et al., in J. Antibiotics 34, 16 (1981), report information on the synthesis and biological activity of both C-3'-epimers of 3'-deoxo-3'-amino-3'-dihydrospectinomycin, which is closely related to the disclosure of U.S. Pat. No. 4,173,647.
Woitun, et al., in J. Antibiotics 34, 22 (1981), a reference not necessarily subsequent to any invention disclosed herein, disclose numerous 3'-substituted amino analogs of 3'-deoxo-3'-(R)-3'-amino-3'-dihydrospectinomycin and its N,N'-di(carbobenzyloxy) analog. The compounds disclosed in the Woitun, et al. reference which are closest to the subject matter of the present invention are illustrated by formula XXVII, wherein R.sub.27 is methyl, ethyl, isopropyl, n-pentyl, n-nonyl, n-dodecyl or n-octadecyl, and formula XXVIII, wherein R.sub.28 is methyl or ethyl. Both compounds represented by formula XXVIII are reported in the Woitun, et al. reference to be inactive as antimicrobial agents.
Hanessian, et al., in J. Antibiotics 34, 350 (1981), another reference not necessarily subsequent to any invention disclosed herein, disclose 3'-deoxo-3'-(S)-methylsulfonyloxy-N,N'-di(carbobenzyloxy)-3'-dihydrospecti nomycin and 3'-deoxo-3'-(S)-3'azido-N,N'-di(carbobenzyloxy)-3'-dihydrospectinomycin (formula XXIX).
Numerous analogs of both 3'-epimers of 3'-dihydrospectinomycin are reported in U.S. patent application Ser. No. 020,073, filed Mar. 13, 1979. The analogs include actinamine-ring-nitrogen unblocked and blocked with a wide variety of blocking groups, 5'-desmethyl compounds and compounds substituted at C-6' with a variety of substituents, including all the C-6' substituents within the scope of the present invention except the nitrogen-containing 6'-substituents in which the nitrogen atom is bonded to a blocking group. The C-3' region of compounds disclosed in U.S. patent application Ser. No. 020,073, filed Mar. 13, 1979, is displayed in formula XXX, wherein R.sub.30 includes hydrogen and alkyl of 1 to 8 carbon atoms, inclusive. Formula XXX is intended to indicate both the 3'-(R) and 3'-(S) stereoisomer of each analog.
No analogs of spectinomycin appear known to the art wherein a halogen or carbon atom is bonded directly to C-3' or wherein a nitrogen atom, where present in a C-6' substituent, is bonded to a blocking group.
Maier, et al., U.S. Pat. No. 4,173,647; Federal Republic of Germany Offenlegungschriften Nos. 2,756,913 (Derwent Farmdoc Accession No. 50960B) and 2,756,914 (Derwent Farmdoc Accession No. 50961B); and Maier, et al., J. Antibiotics 34, 16 (1981) teach the reduction of spectinomycin hydrazones (formulas XXV and XXVI) and oximes to both epimers of 3'-deoxo-3'-amino-3'-dihydrospectinomycins. The references teach the presence of acid is advantageous in the reductions.
Hanessian, et al., J. Antibiotics 34, 350 (1981), discloses reduction by precious metal-catalyzed hydrogenolysis of 3'-deoxo-N,N'-di(carbobenzyloxy)-3'-(S)-3'-azido-3'-dihydrospectinomycin to 3'-deoxo-3'-(S)-3'-amino-3'-dihydrospectinomycin.
House, et al., J. Org. Chem. 33, 53 (1968), teach the formation of diazoacetic acid esters of unsaturated alcohols by the reaction of acetic acid tosylhydrazone esters of unsaturated alcohols with triethylamine in methylene chloride. In view of the known base-sensitivity of spectinomycin and its analogs, as well as the significant structural and chemical differences between the C-3' region of 3'-arylsulfonylhydrazones of spectinomycin and its analogs and the carboxylate-carbon region of acetic acid arylsulfonylhydrazone esters, provide no basis to predicting whether the reaction conditions employed by House, et al., could be used to successfully form 3'-deoxo-3'-diazo-spectinomycin.
There appear to be no examples of reactions between diazo ketones (e.g., in formula XXXI, the C-2'-C-3' region of 3'-deoxo-3'-diazo-spectinomycin), and (N,N-dialkyl)methyleneammonium halides prior to the disclosure herein of such a reaction used to link a carbon atom to the C-3' of spectinomycins by formation of 3'-deoxo-3'-(N,N-dialkyl)-enamino-spectinomycins, which, as shown in the present specification, are valuable as intermediates in synthesis of antimicrobial 3'-analogs of spectinomycin.
A review of hydrocyanation reactions of aldehydes and ketones, and the stereoselectivity thereof, is provided by Mathieu, et al., Formation of C--C Bonds, G. Thieme Publ. Stuttgart, W. Germany, Vol. I, pp. 429-440 (1973). See also Grewe, et al., Chem. Ber. 98, 104 (1965). In accordance with the disclosure herein hydrocyanation occurs at the C-3' ketone in spectinomycins under reaction conditions of novel processes (iii) described briefly above and in greater detail below. The prior art teaches that the 3'-(R)-spectinomycin cyanohydrins would be expected as the predominant products under such reaction conditions. Surprisingly and unexpectedly this kinetically favored product of the hydrocyanation, the 3'-(R)-spectinomycin cyanohydrin, is thermodynamically less stable than the 3'-(S)-epimer.
The known spectinomycin analogs described herein, with the exception of the two compounds of formula XXVIII disclosed by Woitun, et al., J. Antibiotics 34, 22 (1981), for which no utility is described, are asserted in the various references cited to be useful as either antimicrobial agents or intermediates in processes for synthesizing analogs which are antimicrobials. All analogs which have blocking groups on the nitrogens bonded to C-1 and C-3 in the actinamine ring, and all 3'-hydrazone and 3'-oxime analogs, are described to be useful as such intermediates. The other analogs, other than the two of formula XXVIII disclosed in the Woitun, et al. reference, are disclosed to be useful as antimicrobials.